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In present day at New York City, an elderly woman and her granddaughter are walking through Central Park, looking for a memorial statue. As they seat themselves for a rest, the grandmother tells a story about Nome, Alaska, back in 1925 which shifts the film from live-action to animation.

Balto, a wolfdog hybrid, lives on the outskirts of Nome with his best friend and adoptive father, a snow goose named Boris and two polar bears, Muk and Luk. Being half-breed, Balto is ridiculed by dogs and humans alike. His only friend in town is a red husky named Jenna who Balto has a crush on and is challenged by the town's favorite sled dog, Steele, a fierce and arrogant purebred Alaskan Malamute.

That night, all the children, including Jenna's owner, Rosie, began to get sick with diphtheria. Severe winter weather conditions prevent medicine to be brought by air or sea, and the closest rail line ends in Nenana, Alaska. The next day, a dog race is held to determine the best-fit dogs for a sled dog team to get the medicine. Balto enters and wins, but Steele stomps on his paw, causing Balto to growl in pain and bare his teeth, resulting in him being disqualified. The team departs that night with Steele in the lead and picks up the medicine successfully, but on the way back, conditions deteriorate and the disoriented team ends up stranded at the base of a steep slope with the musher knocked unconscious. When the word reaches Nome, Balto sets out in search of them with Boris, Muk and Luk. On the way, they are attacked by a huge grizzly bear, but Jenna, who followed their tracks, arrives to help, though she is injured in the process. The bear pursues Balto out onto a frozen lake, where it falls through the ice and drowns; Balto himself narrowly avoids the same fate with Muk and Luk's help. However, Jenna's injuries mean that she cannot make the journey with the rest of the group. Balto instructs Boris, Muk, and Luk to take her back to Nome while he continues on alone.

Balto eventually finds the team, but Steele refuses his help and a fight ensues, ending with Steele falling off a cliff. Balto takes charge of the team, but Steele, refusing to concede defeat, throws them off the trail and they lose their way again. While attempting to save the medicine from falling down a cliff, Balto himself falls. When he regains consciousness, he is ready to give up hope, but when a large, white wolf appears and he notices the medicine crate still intact nearby, he realizes that his part-wolf heritage is a strength, not a weakness, and drags the medicine back up the cliff to the waiting team. Using his advanced senses, Balto is able to filter out the false markers Steele created.

After encountering further challenges, Balto and the sled team finally make it back to Nome with only losing one vial. A pity-playing Steele is exposed as a liar and is abandoned by the other dogs. Reunited with Jenna and his friends, Balto earns respect from both the dogs and the humans. He visits Rosie who thanks him for the medicine.

Back in the present in New York City, the elderly woman and her granddaughter finally find the memorial commemorating Balto, and she explains that the Iditarod trail covers the same path that Balto and his team took from Nenana to Nome. The woman, who is actually Rosy, looks up at the statue and repeats the same line, "Thank you, Balto. I would have been lost without you," before walking off to join her granddaughter as the sun shines upon the Balto statue.

Juliette Brewer as young Rosy, Jenna's owner and a kind, excitable girl who was the only human in Nome who is kind to Balto. She falls ill, but Balto brings the medicine to save her and the other children. David Bowers served as the supervising animator for Rosy.

Jim Cummings as Steele, an Alaskan Malamute and Balto's rival who also has a crush on Jenna. Sahin Ersöz served as the supervising animator for Steele.

Phil Collins as Muk and Luk, a pair of Polar bear cubs, Muk talks but not Luk. Nicolas Marlet served as the supervising animator for Muk and Luk.

Jack Angel, Danny Mann and Robbie Rist as Nikki, Kaltag and Star, the members of Steele's team. William Salazar served as the supervising animator for the team.

Sandra Dickinson as Dixie, a female Pomeranian and one of Jenna's friends who adores Steele. Dickinson also voices Sylvie, a female Afghan Hound who is Jenna's friend as well; and Rosy's mother. Patrick Mate served as the supervising animator for Sylvie and Dixie.

Lola Bates-Campbell as Rosy's granddaughter, who appears in the live-action sequences and is accompanied by her dog Blaze, purebred Siberian Husky.

The biggest inaccuracy in the film portrays Balto (October, 1919–March, 1933) as a grey wolfdog. In real life, Balto was a pure bred Siberian Husky and was black and white in color.[4][5]

The sled run to retrieve the medicine was a relay. Instead of being the leader of the first team, Balto was the leader of the last team to carry the medicine to Nome. The longest and most hazardous distance was traveled by the team led by Togo.[6][7]

The medicine was never driven by the dogs alone, and none of the mushers were incapacitated.[4]

Balto was never an outcast street dog as shown by the film, but was instead born in a kennel owned by the famous musher Leonhard Seppala, where he was trained until deemed fit for pulling a sled as the lead dog. Seppala was also the owner of Togo (1913–1929), whom he personally used to lead his dog team during the relay. Balto was used by one of Seppala's workers, Gunnar Kaasen.[4][5][6]

Balto is the only animal and the only character in the movie who is based on an actual historical figure.[5]

In the sequels, Balto was shown to have offsprings, but in real life he was neutered at a young age.[5]

In the sequels, Balto continued living in Nome along with his family and friends (the events of the third film happened in 1928), but in the real life, Balto and his team were to the Brookside Zoo (now the Cleveland Metroparks Zoo) in 1927 where they spend their last years.

The film was theatrically released in the United States on 22 December 1995 and then hit international theatres on 13 January 1996 when it first premiered in Brazil.[2] Its release was vastly overshadowed by the performance of Disney•Pixar's Toy Story. But the film did end up recouping its small budget and did modest business at the box office.[3]

The film ranked 15th on its opening weekend and earned $1,519,755 from a total of 1,427 theatres.[8] The film also ranked 7th among G-rated movies in 1995. Total domestic gross reach up to $11,348,324.[3] Strong video sales led to the release of two direct-to-video sequels: Balto II: Wolf Quest and Balto III: Wings of Change.

Two direct-to-video sequels of the film followed, made by the Universal Cartoon Studios. The first sequel, Balto II: Wolf Quest, was released in 2002 and follows the adventures of one of Balto and Jenna's pups, Aleu, who sets off to discover her wolf heritage.[13] A subsequent third film, Balto III: Wings of Change, was released in 2004. The storyline follows the same litter of pups from Balto 2 but focuses on Kodi as part of a U.S. Mail dog sled delivery team.[14] Unlike the original, neither films took any historical references from the true story of Balto.